Differential calcium channel-mediated dopaminergic modulation in the subthalamonigral synapse.

Dopamine (DA) modulates basal ganglia (BG) activity for initiation and execution of goal-directed movements and habits. While most studies are aimed to striatal function, the cellular and molecular mechanisms underlying dopaminergic regulation in other nuclei of the BG are not well understood. Therefore, we set to analyze the dopaminergic modulation occurring in subthalamo-nigral synapse, in both pars compacta (SNc) and pars reticulata (SNr) neurons, because these synapses are important for the integration of information previously processed in striatum and globus pallidus. In this study, electrophysiological and pharmacological evidence of dopaminergic modulation on glutamate release through calcium channels is presented. Using paired pulse ratio (PPR) measurements and selective blockers of these ionic channels, together with agonists and antagonists of DA D2 -like receptors, we found that blockade of the CaV 3 family occludes the presynaptic inhibition produced by the activation of DA receptors pharmacologically profiled as D3 -type in the STh-SNc synapses. On the contrast, the blockade of CaV 2 channels, but not CaV 3, occlude with the effect of the D3 agonist, PD 128907, in the STh-SNr synapse. The functional role of this differential distribution of calcium channels that modulate the release of glutamate in the SN implies a fine adjustment of firing for both classes of neurons. Dopaminergic neurons of the SNc establish a DA tone within the SN based on the excitatory/inhibitory inputs; such tone may contribute to processing information from subthalamic nucleus and could also be involved in pathological DA depletion that drives hyperexcitation of SNr neurons.

Whole course of pallidothalamic tracts identified on the sectioned images and surface models.

The anatomy of the pallidothalamic tracts, including the ansa lenticularis, lenticular fasciculus, and thalamic fasciculus (field H1 of Forel), should be elucidated by neurosurgeons and neuroscientists who study deep brain stimulation. In this study, serially sectioned images of a human cadaver head were employed to overcome the limitations of existing methods to observe the pallidothalamic tracts. Owing to the high resolution and real color of the sectioned images, 28 structures, including the pallidothalamic tracts and mammillothalamic fasciculus, were identified. The structures were segmented and made into surface models, which are helpful in improving the stereoscopic understanding. Observing the sectioned images and surface models may help in understanding the detailed anatomy of the pallidothalamic tracts. The new findings, such as the spatial relationship of the tracts, were summarized in a schematic figure. Moreover, to elucidate the anatomical structures along the course of deep brain stimulation, virtual electrodes were inserted into the surface models. The sectioned images and surface models of this study are expected to enhance the understanding of the pallidothalamic tract anatomy. A portable document format file containing the surface models and the sectioned images can be freely downloaded from the authors' homepage. Clin. Anat. 32:66-76, 2019. © 2019 Wiley Periodicals, Inc.

Gradient subthalamic neurodegeneration and tau pathology in the hypoglossal nucleus as essential pathological markers of progressive supranuclear palsy - Richardson syndrome.

Progressive supranuclear palsy - Richardson syndrome (PSP-RS) was first described in 1964 by Steele et al. Tau pathology has not been reported in the hypoglossal nuclei of PSP-RS patients, whereas Steele et al. described gliosis with no remarkable neuronal losses in the hypoglossal nucleus. This study aimed to investigate the distribution and degree of tau pathology-associated neurodegeneration, with an emphasis on the hypoglossal nucleus, in patients with PSP-RS. Six clinicopathologically proven PSP-RS cases were included in this study. All patients were clinicopathologically and immunohistochemically re-evaluated. This study confirmed the following neuropathological characteristics of PSP-RS: (1) neurodegeneration usually affects the striatonigral system and cerebellar dentate nucleus; (2) the cerebellar afferent system in PSP-RS is affected by absent-to-mild neurodegeneration; and (3) the extent of tau distribution throughout the central nervous system is greater than the extent of neurodegeneration. Furthermore, we found that subthalamic neurodegeneration was more prominent in the ventromedial region than in the dorsolateral region. Nevertheless, the tau pathology showed no remarkable differences between these two sites. Interestingly, the tau pathology was frequently observed in the hypoglossal nuclei of PSP-RS patients. Gradient neurodegeneration of the subthalamus and tau pathology in the hypoglossal nucleus could be regarded as essential pathological features of PSP-RS.

Transient increased thalamic-sensory connectivity and decreased whole-brain dynamism in autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with social communication deficits and restricted/repetitive behaviors and is characterized by large-scale atypical subcortical-cortical connectivity, including impaired resting-state functional connectivity between thalamic and sensory regions. Previous studies have typically focused on the abnormal static connectivity in ASD and overlooked potential valuable dynamic patterns in brain connectivity. However, resting-state brain connectivity is indeed highly dynamic, and abnormalities in dynamic brain connectivity have been widely identified in psychiatric disorders. In this study, we investigated the dynamic functional network connectivity (dFNC) between 51 intrinsic connectivity networks in 170 individuals with ASD and 195 age-matched typically developing (TD) controls using independent component analysis and a sliding window approach. A hard clustering state analysis and a fuzzy meta-state analysis were conducted respectively, for the exploration of local and global aberrant dynamic connectivity patterns in ASD. We examined the group difference in dFNC between thalamic and sensory networks in each functional state and group differences in four high-dimensional dynamic measures. The results showed that compared with TD controls, individuals with ASD show an increase in transient connectivity between hypothalamus/subthalamus and some sensory networks (right postcentral gyrus, bi paracentral lobule, and lingual gyrus) in certain functional states, and diminished global meta-state dynamics of the whole-brain functional network. In addition, these atypical dynamic patterns are significantly associated with autistic symptoms indexed by the Autism Diagnostic Observation Schedule. These converging results support and extend previous observations regarding hyperconnectivity between thalamic and sensory regions and stable whole-brain functional configuration in ASD. Dynamic brain connectivity may serve as a potential biomarker of ASD and further investigation of these dynamic patterns might help to advance our understanding of behavioral differences in this complex neurodevelopmental disorder.

Biophysical basis of subthalamic local field potentials recorded from deep brain stimulation electrodes.

Clinical deep brain stimulation (DBS) technology is evolving to enable chronic recording of local field potentials (LFPs) that represent electrophysiological biomarkers of the underlying disease state. However, little is known about the biophysical basis of LFPs, or how the patient's unique brain anatomy and electrode placement impact the recordings. Therefore, we developed a patient-specific computational framework to analyze LFP recordings within a clinical DBS context. We selected a subject with Parkinson's disease implanted with a Medtronic Activa PC+S DBS system and reconstructed their subthalamic nucleus (STN) and DBS electrode location using medical imaging data. The patient-specific STN volume was populated with 235,280 multicompartment STN neuron models, providing a neuron density consistent with histological measurements. Each neuron received time-varying synaptic inputs and generated transmembrane currents that gave rise to the LFP signal recorded at DBS electrode contacts residing in a finite element volume conductor model. We then used the model to study the role of synchronous beta-band inputs to the STN neurons on the recorded power spectrum. Three bipolar pairs of simultaneous clinical LFP recordings were used in combination with an optimization algorithm to customize the neural activity parameters in the model to the patient. The optimized model predicted a 2.4-mm radius of beta-synchronous neurons located in the dorsolateral STN. These theoretical results enable biophysical dissection of the LFP signal at the cellular level with direct comparison to the clinical recordings, and the model system provides a scientific platform to help guide the design of DBS technology focused on the use of subthalamic beta activity in closed-loop algorithms. NEW & NOTEWORTHY The analysis of deep brain stimulation of local field potential (LFP) data is rapidly expanding from scientific curiosity to the basis for clinical biomarkers capable of improving the therapeutic efficacy of stimulation. With this growing clinical importance comes a growing need to understand the underlying electrophysiological fundamentals of the signals and the factors contributing to their modulation. Our model reconstructs the clinical LFP from first principles and highlights the importance of patient-specific factors in dictating the signals recorded.

Altered functional connectivity of the subthalamus and the bed nucleus of the stria terminalis in obsessive-compulsive disorder.

BACKGROUND: The assessment of inter-regional functional connectivity (FC) has allowed for the description of the putative mechanism of action of treatments such as deep brain stimulation (DBS) of the nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Nevertheless, the possible FC alterations of other clinically-effective DBS targets have not been explored. Here we evaluated the FC patterns of the subthalamic nucleus (STN) and the bed nucleus of the stria terminalis (BNST) in patients with OCD, as well as their association with symptom severity. METHODS: Eighty-six patients with OCD and 104 healthy participants were recruited. A resting-state image was acquired for each participant and a seed-based analysis focused on our two regions of interest was performed using statistical parametric mapping software (SPM8). Between-group differences in FC patterns were assessed with two-sample t test models, while the association between symptom severity and FC patterns was assessed with multiple regression analyses. RESULTS: In comparison with controls, patients with OCD showed: (1) increased FC between the left STN and the right pre-motor cortex, (2) decreased FC between the right STN and the lenticular nuclei, and (3) increased FC between the left BNST and the right frontopolar cortex. Multiple regression analyses revealed a negative association between clinical severity and FC between the right STN and lenticular nucleus. CONCLUSIONS: This study provides a neurobiological framework to understand the mechanism of action of DBS on the STN and the BNST, which seems to involve brain circuits related with motor response inhibition and anxiety control, respectively.

Neuropsychological performance changes following subthalamic versus pallidal deep brain stimulation in Parkinson's disease: a systematic review and metaanalysis.

BACKGROUND: Studies comparing subthalamus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) for the management of Parkinson's disease in terms of neuropsychological performance are scarce and heterogeneous. Therefore, we performed a systematic review and metaanalysis to compare neuropsychological outcomes following STN DBS versus GPi DBS. METHODS: A computer literature search of PubMed, the Web of Science, and Cochrane Central was conducted. Records were screened for eligible studies, and data were extracted and synthesized using Review Manager (v. 5.3 for Windows). RESULTS: Seven studies were included in the qualitative synthesis. Of them, four randomized controlled trials (n=345 patients) were pooled in the metaanalysis models. The standardized mean difference (SMD) of change in the Stroop color-naming test favored the GPi DBS group (SMD=-0.31, p=0.009). However, other neuropsychological outcomes did not favor either of the two groups (Stroop word-reading: SMD=-0.21, p=0.08; the Wechsler Adult Intelligence Scale (WAIS) digits forward: SMD=0.08, p=0.47; Trail Making Test Part A: SMD=-0.05, p=0.65; WAIS-R digit symbol: SMD=-0.16, p=0.29; Trail Making Test Part B: SMD=-0.14, p=0.23; Stroop color-word interference: SMD=-0.16, p=0.18; phonemic verbal fluency: bilateral DBS SMD=-0.04, p=0.73, and unilateral DBS SMD=-0.05, p=0.83; semantic verbal fluency: bilateral DBS SMD=-0.09, p=0.37, and unilateral DBS SMD=-0.29, p=0.22; Boston Naming Test: SMD=-0.11, p=0.33; Beck Depression Inventory: bilateral DBS SMD=0.15, p=0.31, and unilateral DBS SMD=0.36, p=0.11). CONCLUSIONS: There was no statistically significant difference in most of the neuropsychological outcomes. The present evidence does not favor any of the targets in terms of neuropsychological performance.

Long-Term Results of Deep Brain Stimulation of the Mamillotegmental Fasciculus in Chronic Cluster Headache.

BACKGROUND: Deep brain stimulation (DBS) and the proper target for chronic cluster headache (CCH) are still subjects of controversy. OBJECTIVES: We present our long-term results of analysis of the target and its structural connectivity. METHODS: Fifteen patients with drug-resistant CCH underwent DBS in coordinates 4 mm lateral to the III ventricular wall and 2 mm behind and 5 mm below the intercommissural point. The clinical parameters recorded were the number of weekly attacks, pain intensity, and duration of the headache. Structural connectivity was studied using 3-T MR diffusion tensor imaging (DTI). RESULTS: All of our patients improved from a mean of 39 attacks/week to 2; pain intensity decreased from 9 to 3 out of 10, and the mean cephalalgia duration decreased from 53 to 8 min. The mean stereotactic coordinates of the effective contact location were 6.1 mm lateral to the midcommissural point and 1.2 mm behind and 4.0 mm below the intercommissural point. DTI analysis showed that this target was connected to tracts and nuclei of the posterior mesencephalic tegmentum, specifically the dorsal longitudinal and mamillotegmental fasciculi. CONCLUSIONS: Our data showed DBS to be a safe and useful procedure for the treatment of drug-resistant CCH; the rate of improvement was higher than those found in other series. Although these are promising results, larger series targeting those fasciculi with a longer follow-up are needed.

Coaxial interleaved stimulation of the thalamus and subthalamus for treatment of Holmes tremor.

Holmes tremor is often treated with multiple deep brain stimulation (DBS) electrodes. The authors describe a novel technique to suppress the tremors by effectively utilizing a single electrode. A 16-year-old boy presented with severe right arm tremor following a midbrain injury. A DBS electrode was implanted into the ventral oralis nucleus of the thalamus (VO) and the subthalamic region. While individual stimulation of each target was ineffective, an interleaved dual stimulation of both targets has been effective for 6 years. Coaxial interleaved stimulation of the VO and the subthalamic region is useful for treating Holmes tremor. The video can be found here: https://youtu.be/tSwGh3vy68c .

Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease.

Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico-cortical coherence in the beta band was significantly attenuated over the bilateral sensorimotor areas. Similarly, the global cortico-cortical phase synchronization was attenuated, and the topographic differentiation revealed stronger desynchronization over the (ipsilateral) right-hemispheric prefrontal, premotor and sensorimotor areas compared to 'stimulation off'. We further demonstrated that the cortico-cortical phase synchronization was largely dominated by genuine neuronal coupling. The clinical improvement with 'stimulation on' compared to 'stimulation off' could be predicted from this cortical decoupling with multiple regressions, and the reduction of synchronization over the right prefrontal area showed a linear univariate correlation with clinical improvement. Our study demonstrates wide-spread activity and synchronization modulations of the cortical motor network, and highlights subthalamic stimulation as a network-modulating therapy. Accordingly, subthalamic stimulation may release bilateral cortical computational resources by facilitating movement-related desynchronization. Moreover, the subthalamic nucleus is critical to balance inhibitory and facilitatory cortical players within the motor program.

Motivational tuning of fronto-subthalamic connectivity facilitates control of action impulses.

It is critical for survival to quickly respond to environmental stimuli with the most appropriate action. This task becomes most challenging when response tendencies induced by relevant and irrelevant stimulus features are in conflict, and have to be resolved in real time. Inputs from the pre-supplementary motor area (pre-SMA) and inferior frontal gyrus (IFG) to the subthalamic nucleus (STN) are thought to support this function, but the connectivity and causality of these regions in calibrating motor control has not been delineated. In this study, we combined off-line noninvasive brain stimulation and functional magnetic resonance imaging, while young healthy human participants performed a modified version of the Simon task. We show that impairing pre-SMA function by noninvasive brain stimulation improved control over impulsive response tendencies, but only when participants were explicitly rewarded for fast and accurate responses. These effects were mediated by enhanced activation and connectivity of the IFG-STN pathway. These results provide causal evidence for a pivotal role of the IFG-STN pathway during action control. Additionally, they suggest a parallel rather than hierarchical organization of the pre-SMA-STN and IFG-STN pathways, since interruption of pre-SMA function can enhance IFG-STN connectivity and improve control over inappropriate responses.

Subjectively perceived personality and mood changes associated with subthalamic stimulation in patients with Parkinson's disease.

BACKGROUND: Clinical and ethical implications of personality and mood changes in Parkinson's disease (PD) patients treated with subthalamic deep brain stimulation (STN-DBS) are under debate. Although subjectively perceived personality changes are often mentioned by patients and caregivers, few empirical studies concerning these changes exist. Therefore, we analysed subjectively perceived personality and mood changes in STN-DBS PD patients. METHOD: In this prospective study of the ELSA-DBS group, 27 PD patients were assessed preoperatively and 1 year after STN-DBS surgery. Two categories, personality and mood changes, were analysed with semi-structured interviews. Patients were grouped into personality change yes/no, as well as positive/negative mood change groups. Caregivers were additionally interviewed about patients' personality changes. Characteristics of each group were assessed with standard neurological and psychiatric measurements. Predictors for changes were analysed. RESULTS: Personality changes were perceived by six of 27 (22%) patients and by 10 of 23 caregivers (44%). The preoperative hypomania trait was a significant predictor for personality change perceived by patients. Of 21 patients, 12 (57%) perceived mood as positively changed. Higher apathy and anxiety ratings were found in the negative change group. CONCLUSIONS: Our results show that a high proportion of PD patients and caregivers perceived personality changes under STN-DBS, emphasizing the relevance of this topic. Mood changed in positive and negative directions. Standard measurement scales failed to adequately reflect personality or mood changes subjectively perceived by patients. A more individualized preoperative screening and preparation for patients and caregivers, as well as postoperative support, could therefore be useful.

White matter alterations in patients with MRI-negative temporal lobe epilepsy and their asymptomatic siblings.

OBJECTIVE: The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy. METHODS: We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gender-matched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs). RESULTS: Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset. SIGNIFICANCE: These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusion-based endophenotype in the disorder. Further studies of narrow-sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results.

Optimizing Prelemniscal Radiations as a Target for Motor Symptoms in Parkinson's Disease Treatment.

OBJECTIVE: To better define prelemniscal radiations (Raprl) as a target for the control of tremor and rigidity in Parkinson's disease (PD). METHODS: A total of 36 deep brain stimulation (DBS) electrodes were stereotactically implanted in Raprl contralateral to the extremities to be treated. Effects on symptoms were evaluated using UPDRS-III before and after DBS, and significance was determined using the Wilcoxon test. The location of DBS contacts in cases with optimum versus suboptimum results was evaluated using Student's t test and percentage improvement correlated through a bivariable Pearson test. The power and percentage of spike components for microelectrode recordings were statistically compared between the target point and structures located above and below. RESULTS: Raprl-DBS improved tremor and rigidity (p < 0.01). The potency of microelectrode recordings indicated that the target was formed by fibers. There was no correlation between demographic characteristics and clinical outcome, and there were no significant differences in stereotactic placement between cases with optimum and suboptimum results. Tremor and rigidity were selectively improved in cases with suboptimum results. CONCLUSION: Raprl-DBS is an effective treatment for the motor symptoms of PD. Selective improvement of symptoms suggests that the target has different fiber components related to either tremor or rigidity, and variations in improvement between cases may derive from individual variations of the location of these fibers.

Serotonin regulation of subthalamic neurons.

The subthalamic nucleus (STN) is a key component of the basal ganglia. As the only basal ganglia nucleus comprised of mostly glutamatergic neurons, STN neurons provide a key driving force to their target neurons. Thus, regulation of STN neuron activity is important. One STN regulator is the serotonin (5-HT) system. The STN receives a dense 5-HT innervation. 5-HT1A, 5-HT1B, 5-HT2C, and 5-HT4 receptors are expressed in the STN. 5-HT may regulate the STN via several mechanisms. First, 5-HT may affect STN neuron excitability directly by either inhibiting a subpopulation of STN neurons via activation of 5-HT1A receptors or exciting STN neurons through activation of 5-HT2C and 5-HT4 receptors. Second, 5-HT may affect synaptic inputs to the STN. Via activation of 5-HT1B receptors on the afferent terminals, 5-HT inhibits glutamatergic input to the STN, but the inhibitory effect on GABAergic input is smaller. Third, 5-HT may regulate the STN glutamatergic output by activating presynaptic 5-HT1B receptors, thus reducing burst firing in target neurons. Last, 5-HT may affect glutamate release at the intra-STN axon collaterals and regulate the recurrent excitation. These mechanisms may work in concert to fine-tune the intensity and pattern of STN activity and reduce STN output bursts.

Dissociable dorsal and ventral frontostriatal working memory circuits: evidence from subthalamic stimulation in Parkinson's disease.

In this study, we investigated the neural substrates involved in visual working memory (WM) and the resulting effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD). Cerebral activation revealed by positron emission tomography was compared among Parkinson patients with (PD-ON) or without (PD-OFF) STN stimulation, and a group of control subjects (CT) in two visual WM tasks with spatial (SP) and nonspatial (NSP) components. PD-OFF patients displayed significant reaction time (RT) deficits for both memory tasks. Although there were no significant differences in RT between patients with PD-ON and -OFF stimulation, patients with PD-ON stimulation performed comparably to controls. The memory tasks were executed with normal error rates in PD-ON and -OFF stimulation. In contrast to these behavioral results, whether the corresponding prefrontal activation was differentially affected by deep brain stimulation status in patients depended on whether the WM modality was SP versus NSP. Thus, SP WM was associated with (1) abnormal reduction in dorsolateral prefrontal activity in PD-OFF and -ON stimulation and (2) abnormal overactivation in parieto-temporal cortex in PD-OFF and in limbic circuits in PD-ON stimulation. In NSP WM, normal activation of the ventral prefrontal cortex was restored in PD-ON stimulation. In both visual modalities the posterior cerebral regions including fusiform cortex and cerebellum, displayed abnormally reduced activity in PD. These results indicate that PD induces a prefrontal hypoactivation that STN stimulation can partially restore in a modality selective manner by additional recruitment of limbic structures in SP WM or by recovery of the ventral prefrontal activation in NSP WM.

The anatomy of the caudal zona incerta in rodents and primates.

The caudal zona incerta is the target of a recent modification of established procedures for deep brain stimulation (DBS) for Parkinson's disease and tremor. The caudal zona incerta contains a number of neuronal populations that are distinct in terms of their cytoarchitecture, connections, and pattern of immunomarkers and is located at a position where a number of major tracts converge before turning toward their final destination in the forebrain. However, it is not clear which of the anatomical features of the region are related to its value as a target for DBS. This paper has tried to identify features that distinguish the caudal zona incerta of rodents (mouse and rat) and primates (marmoset, rhesus monkey, and human) from the remainder of the zona incerta. We studied cytoarchitecture, anatomical relationships, the pattern of immunomarkers, and gene expression in both of these areas. We found that the caudal zona incerta has a number of histological and gene expression characteristics that distinguish it from the other subdivisions of the zona incerta. Of particular note are the sparse population of GABA neurons and the small but distinctive population of calbindin neurons. We hope that a clearer appreciation of the anatomy of the region will in the end assist the interpretation of cases in which DBS is used in human patients.

Deep brain stimulation in the treatment of Holmes tremor - a long-term case observation.

We present the patient with Holmes tremor secondary to the infarction of thalamus, successfully treated with the deep brain stimulation (DBS) of the area between ventralis oralis anterior and zona incerta for a long time, in whom the severe tremor reappeared after removal of the DBS lead. This is the first presentation of the effective DBS on this location. Our case does not support the hypothesis that the DBS treatment could lead to sustained relief of symptoms after cessation of stimulation.

The zona incerta modulates spontaneous spike-wave discharges in the rat.

The contribution of the zona incerta (ZI) of the thalamus on spike-wave discharges (SWDs) was investigated. Chronic recordings of bilateral cortices, bilateral vibrissa muscle, and unilateral ZI were performed in Long-Evans rats to examine the functional role of SWDs. Rhythmic ZI activity appeared at the beginning of SWD and was accompanied by higher-oscillation frequencies and larger spike magnitudes. Bilateral lidocaine injections into the mystacial pads led to a decreased oscillation frequency of SWDs, but the phenomenon of ZI-related spike magnitude enhancement was preserved. Moreover, 800-Hz ZI microstimulation terminates most of the SWDs and whisker twitching (WT; >80%). In contrast, 200-Hz ZI microstimulation selectively stops WTs but not SWDs. Stimulation of the thalamic ventroposteriomedial nucleus showed no obvious effect on terminating SWDs. A unilateral ZI lesion resulted in a significant reduction of 7- to 12-Hz power of both the ipsilateral cortical and contralateral vibrissae muscle activities during SWDs. Intraincertal microinfusion of muscimol showed a significant inhibition on SWDs. Our present data suggest that the ZI actively modulates the SWD magnitude and WT behavior.